||The effect of NERP-1 and NERP-2, two recently discovered VGF-derived peptides, on feeding and penile erection was studied after injection into the lateral ventricles, the lateral hypothalamus, the arcuate nucleus or the paraventricular nucleus of the hypothalamus. NERP-2 (1-5nmol), but not NERP-1 (2-4nmol), increased feeding in a dose-dependent manner when injected into the lateral ventricles or bilaterally into the lateral hypothalamus but not into the arcuate or the paraventricular nucleus. The effect of NERP-2 given into the lateral ventricles was found in the first, but not in the second 60min after treatment, and was antagonized by SB-408124, an orexin-1 receptor antagonist given into the lateral ventricles or the arcuate nucleus, but not into the paraventricular nucleus. However, SB-408124 was unable to reduce NERP-2-induced feeding when injected bilaterally into the lateral hypothalamus before NERP-2 given also bilaterally into the lateral hypothalamus. In contrast, NERP-1, but not NERP-2, induced penile erection in a dose-dependent manner when injected into the lateral ventricles or the arcuate nucleus, but not into the paraventricular nucleus or the lateral hypothalamus. The pro-erectile effect of NERP-1 was not prevented by the prior injection of d(CH(2))(5)Tyr (Me)(2)-Orn(8)-oxytocin or SB-408124 into the lateral ventricles. The present results suggest that while NERP-2 facilitates feeding by acting in the lateral hypothalamus, possibly by increasing orexin activity in the arcuate nucleus, NERP-1 facilitates penile erection by acting in the arcuate nucleus with a mechanism not related to orexin or oxytocin.